DESCRIPTION (Adapted from Investigators' Abstract): The long-term goal of this research is to determine the relative contributions of genetic and environmental factors in the etiology of typical Parkinson's disease (PD) by comparing concordance rates in MZ and DZ twin pairs, at least one of whom has Parkinson's disease. This proposal extends our recent results in an irreplaceable cohort, the NAS/NRC World War II Veteran Twins cohort, which showed nearly identical concordance rates in monozygotic and dizygotic twin pairs with typical late onset (over age 50) Parkinson's Disease. These results strongly implicate environmental factors in the pathogenesis of Parkinson's disease, since one would expect monozygotic twins to show a much higher concordance rate than dizygotic twins if Parkinson's Disease were genetically determined. However, without follow-up we cannot be certain that unaffected cotwins would not have eventually developed the disease, thus changing the study outcome. We propose to assess the presence of both clinical parkinsonism and abnormal striatal dopamine function in twin pairs discordant for Parkinson's disease, and to compare concordance rates by zygosity. Aim 1 will determine if long-term follow-up will change Parkinson's disease concordance ratios in monozygotic and dizygotic twins. We expect to add at least 100 newly diagnosed twin pairs and to re-assess diagnosis in 140 prevalent discordant pairs. The second aim will be to compare the concordance rates in monozygotic twins and dizygotic twins, for either Parkinson's disease or abnormal striatal dopamine function as measured using dopamine transporter imaging with [123I]beta-CIT (2beta-carbomethoxy-3beta-(4-iodophenyl) and SPECT. In the third aim, we will compare concordance rates by zygosity for an abnormal rate of decline in striatal dopamine function. The mean annual decline in striatal dopamine uptake will be estimated by using [123I]beta-CIT uptake separated by, on average, two years. These studies, by virtue of utilizing both clinical and imaging measures, should determine clearly and beyond a doubt if the earlier twins study was flawed by virtue of missing pre-clinical cases of Parkinson's disease. This in turn could help set the research agenda on the cause of Parkinson's disease for years to come.